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EP1838854B1 - Antibodies that recognize Beta Amyloid Peptide - Google Patents

Antibodies that recognize Beta Amyloid Peptide Download PDF

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Publication number
EP1838854B1
EP1838854B1 EP05854278A EP05854278A EP1838854B1 EP 1838854 B1 EP1838854 B1 EP 1838854B1 EP 05854278 A EP05854278 A EP 05854278A EP 05854278 A EP05854278 A EP 05854278A EP 1838854 B1 EP1838854 B1 EP 1838854B1
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Prior art keywords
antibody
antibodies
human
residue
binding fragment
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English (en)
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EP1838854A2 (en
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Guriq Basi
Jack Steven Jacobson
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Janssen Sciences Ireland ULC
Wyeth LLC
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Janssen Alzheimer Immunotherapy
Wyeth LLC
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/34—Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
    • C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value

Definitions

  • the humanized immunoglobulin light chain comprises (i) the variable region complementarity determining regions (CDRs) from the 15C11 immunoglobulin light chain variable region sequence set forth as SEQ ID NO:2, and (ii) a variable framework region from a human acceptor immunoglobulin light chain sequence, optionally having at least one framework residue substituted with the corresponding amino acid residue from the mouse 15C11 light chain variable region sequence, wherein the framework residue is a residue capable of affecting light chain variable region conformation or function as identified by analysis of a three-dimensional model of the 15C11 immunoglobulin light chain variable region.
  • CDRs variable region complementarity determining regions
  • immunoglobulins of the invention comprise pegylated antibody fragments, e.g ., Fabs and Fab's. In yet other embodiments, immunoglobulins of the invention comprise an aglycosylated constant region. In an exemplary embodiment, an immunoglobulin includes an amino acid substitution of an asparagine at position 297 to an alanine, thereby preventing glycosylation of the immunoglobulin.
  • the antibody or antigen binding fragment specifically binds to beta amyloid peptide (A ⁇ ) with a binding affinity of at least 10 -7 M. In yet another embodiment, the antibody or antigen binding fragment specifically binds to beta amyloid peptide (A ⁇ ) with a binding affinity of at least 10 -8 M. In another embodiment, the antibody or antigen binding fragment specifically binds to beta amyloid peptide (A ⁇ ) with a binding affinity of at least 10 -9 M.
  • the invention pertains to a humanized antibody or fragment thereof comprising the complementarity determining regions (CDR1, CDR2 and CDR3) of the 15C11 variable light chain sequence set forth as SEQ ID NO:2 and comprising the complementarity determining regions (CDR1, CDR2 and CDR3) of the 15C11 variable heavy chain sequence set forth as SEQ ID NO:4.
  • the invention pertains to a chimeric immunoglobulin comprising variable region sequence substantially as set forth in SEQ ID NO:2 or SEQ ID NO:4, and constant region sequences from a human immunoglobulin.
  • the disclosure also pertains to a method of preventing or treating an amyloidogenic disease in a patient, comprising administering to the patient an effective dosage of the humanized immunoglobulin described herein.
  • the invention pertains to a pharmaceutical composition
  • a pharmaceutical composition comprising an immunoglobulin molecule described herein and a pharmaceutical carrier.
  • the first, second and third light chain CDRs comprise: amino acids 24-39 of SEQ ID NO:2, amino acids 55-61 of SEQ ID NO:2 and amino acids 94-101 of SEQ ID NO:2, respectively.
  • the first, second and third heavy chain CDRs comprise: amino acids 26-35 of SEQ ID NO:4, amino acids 50-66 of SEQ ID NO:4 and amino acids 99-101 of SEQ ID NO:4, respectively.
  • the disclosure also pertains to a method of imaging amyloid deposits in the brain of a patient comprising administering to the patient an agent that specifically binds to A ⁇ , and detecting the antibody bound to A ⁇ .
  • the agent is an antibody comprising a light chain variable sequence as set forth in SEQ ID NO:2 and a heavy chain variable region sequence as set forth in SEQ ID NO:4, or an antigen-binding fragment of said antibody.
  • the antigen-binding fragment is a Fab fragment
  • the patient has or is at risk for an A ⁇ -related disease or disorder. In another embodiment, the patient has or is at risk for an amyloidogenic disease or disorder. In another embodiment, the patient has or is at risk for Alzheimer's disease.
  • substantially from a human acceptor immunoglobulin means that the majority or key framework residues are from the human acceptor sequence, allowing however, for substitution of residues at certain positions with residues selected to improve or do not diminish activity of the humanized immunoglobulin (e.g ., alter activity such that it more closely mimics the activity of the donor immunoglobulin) or selected to decrease the immunogenicity of the humanized immunoglobulin.
  • the invention features, in addition to the substitutions described above, a substitution of at least one rare human framework residue.
  • a rare residue can be substituted with an amino acid residue which is common for human variable chain sequences at that position.
  • a rare residue can be substituted with a corresponding amino acid residue from a homologous germline variable chain sequence.
  • the immunoglobulins described herein are particularly suited for use in therapeutic methods aimed at preventing or treating amyloidogenic diseases and/or the symptoms and/or behavioral deficits associated with amyloidogenic diseases or disorders.
  • the invention features a method of preventing or treating an amyloidogenic disease (e.g ., Alzheimer's disease) that involves administering to the patient an effective dosage of a humanized immunoglobulin as described herein.
  • an amyloidogenic disease e.g ., Alzheimer's disease
  • the invention features pharmaceutical compositions that include a humanized immunoglobulin as described herein and a pharmaceutical carrier. Also featured are isolated nucleic acid molecules, vectors and host cells for producing the immunoglobulins or immunoglobulin fragments or chains described herein, as well as methods for producing said immunoglobulins, immunoglobulin fragments or immunoglobulin chains
  • the present disclosure further features a method for identifying 15C11 amino acid residues amenable to substitution when producing a humanized immunoglobulin.
  • a method for identifying variable framework region residues amenable to substitution involves modeling the three-dimensional structure of a variable region on a solved homologous immunoglobulin structure and analyzing said model for residues capable of affecting immunoglobulin variable region conformation or function, such that residues amenable to substitution are identified.
  • the disclosure further features use of the variable region sequence set forth as SEQ ID NO:2, 4, or any portion thereof ( or portions thereof), in producing a three-dimensional image of a immunoglobulin, immunoglobulin chain, or domain thereof.
  • ⁇ -amyloid protein includes peptides resulting from secretase cleavage of APP and synthetic peptides having the same or essentially the same sequence as the cleavage products.
  • a ⁇ peptides of the invention can be derived from a variety of sources, for example, tissues, cell lines, or body fluids (e.g. sera or cerebrospinal fluid).
  • neurodegenerative disease refers broadly to disorders or diseases associated with or characterized by degeneration of neurons and/or nervous tissues, e.g . an amyloidogenic disease.
  • ⁇ -amyloid protein e.g ., wild-type, variant, or truncated ⁇ -amyloid protein
  • ⁇ -amyloid protein is the principal polypeptide component of the amyloid deposit.
  • Alzheimer's disease is an example of a "disease characterized by deposits of A ⁇ " or a "disease associated with deposits of A ⁇ ", e.g ., in the brain of a subject or patient.
  • cognitive disorder refers to a deficiency or impairment in one or more cognitive mental processes of a patient.
  • Cognitive deficits may have a number of origins: a functional mechanism (anxiety, depression), physiological aging (age-associated memory impairment), brain injury, psychiatric disorders (e.g . schizophrenia), drugs, infections, toxicants, or anatomical lesions.
  • exemplary cognitive deficits include deficiency or impairment in learning or memory (e.g., in short-term or long term learning and/or memory loss of intellectual abilities, judgment, language, motor skills, and/or abstract thinking).
  • dementia disorder refers to a disorder characterized by dementia (i.e ., general deterioration or progressive decline of cognitive abilities or dementia-like symptoms).
  • Dementia disorders are often associated with, or caused by, one or more aberrant processes in the brain or central nervous system (e.g. neurodegeneration). Dementia disorders commonly progress from mild through severe stages and interfere with the ability of a patient to function independently in everyday life. Dementia may be classified as cortical or subcortical depending on the area of the brain affected. Dementia disorders do not include disorders characterized by a loss of consciousness (as in delirium) or depression, or other functional mental disorders (pseudodementia).
  • animal model or "model animal”, as used herein, includes a member of a mammalian species such as rodents, non-human primates, sheep, dogs, and cows that exhibit features or characteristics of a certain system of disease or disorder, e.g ., a human system, disease or disorder.
  • exemplary non-human animals selected from the rodent family include rabbits, guinea pigs, rats and mice, most preferably mice.
  • An "animal model” of, or “model animal” having, a dementia disorder exhibits, for example, prominent cognitive deficits associated with a dementia-related disorder (e.g ., AD).
  • the model animal Preferably the model animal exhibits a progressive worsening of the cognitive deficit with increasing age, such that the disease progression in the model animal parallels the disease progression in a patient suffering from the dementia disorder.
  • single-chain immunoglobulin or “single-chain antibody” (used interchangeably herein) refers to a protein having a two-polypeptide chain structure consisting of a heavy and a light chain, said chains being stabilized, for example, by interchain peptide linkers, which has the ability to specifically bind antigen.
  • domain refers to a globular region of a heavy or light chain polypeptide comprising peptide loops ( e.g ., comprising 3 to 4 peptide loops) stabilized, for example, by ⁇ -pleated sheet and/or intrachain disulfide bond.
  • Binding fragments are produced by recombinant DNA techniques, or by enzymatic or chemical cleavage of intact immunoglobulins. Binding fragments include Fab, Fab', F(ab') 2 , Fabc, Fv, single chains, and single-chain antibodies. Other than “bispecific” or “bifunctional” immunoglobulins or antibodies, an immunoglobulin or antibody is understood to have each of its binding sites identical. A “bispecific” or “bifunctional antibody” is an artificial hybrid antibody having two different heavy/light chain pairs and two different binding sites. Bispecific antibodies can be produced by a variety of methods including fusion of hybridomas or linking of Fab' fragments. See, e.g. , Songsivilai & Lachmann, Clin. Exp. Immunol. 79:315-321 (1990 ); Kostelny et al., J. Immunol. 148, 1547-1553 (1992 ).
  • humanized variable region refers to a variable region that includes a variable framework region substantially from a human immunoglobulin or antibody and complementarity determining regions (CDRs) substantially from a non-human immunoglobulin or antibody.
  • CDRs complementarity determining regions
  • corresponding region refers to a region or residue on a second amino acid or nucleotide sequence which occupies the same ( i.e. , equivalent) position as a region or residue on a first amino acid or nucleotide sequence, when the first and second sequences are optimally aligned for comparison purposes.
  • significant identity means that two polypeptide sequences, when optimally aligned, such as by the programs GAP or BESTFIT using default gap weights, share at least 60-70% sequence identity, more preferably at least 70-80% sequence identity, more preferably at least 80-90% identity, even more preferably at least 90-95% identity, and even more preferably at least 95% sequence identity or more (e.g., 99% sequence identity or more).
  • substantially identity means that two polypeptide sequences, when optimally aligned, such as by the programs GAP or BESTFIT using default gap weights, share at least 80-90% sequence identity, preferably at least 90-95% sequence identity, and more preferably at least 95% sequence identity or more ( e.g. , 99% sequence identity or more).
  • sequence comparison typically one sequence acts as a reference sequence, to which test sequences are compared.
  • test and reference sequences are input into a computer, subsequence coordinates are designated, if necessary, and sequence algorithm program parameters are designated.
  • sequence comparison algorithm then calculates the percent sequence identity for the test sequence(s) relative to the reference sequence, based on the designated program parameters.
  • a mutation e.g., a backmutation
  • a mutation is said to substantially affect the ability of a heavy or light chain to direct antigen binding if it affects (e.g., decreases) the binding affinity of an intact immunoglobulin or antibody (or antigen binding fragment thereof) comprising said chain by at least an order of magnitude compared to that of the antibody (or antigen binding fragment thereof) comprising an equivalent chain lacking said mutation.
  • epitopes refers to a site on an antigen to which an immunoglobulin or antibody (or antigen binding fragment thereof) specifically binds.
  • Epitopes can be formed both from contiguous amino acids or noncontiguous amino acids juxtaposed by tertiary folding of a protein. Epitopes formed from contiguous amino acids are typically retained on exposure to denaturing solvents, whereas epitopes formed by tertiary folding are typically lost on treatment with denaturing solvents.
  • An epitope typically includes at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 amino acids in a unique spatial conformation.
  • An epitope is also recognized by immunologic cells, for example, B cells and/or T cells.
  • Cellular recognition of an epitope can be determined by in vitro assays that measure antigen-dependent proliferation, as determined by 3 H-thymidine incorporation, by cytokine secretion, by antibody secretion, or by antigen-dependent killing (cytotoxic T lymphocyte assay).
  • N-terminal epitope is an epitope or antigenic determinant comprising residues located within the N-terminus of A ⁇ peptide.
  • Exemplary N-terminal epitopes include residues within amino acids 1-10 of A ⁇ , preferably from residues 1-3, 1-4, 1-5,1-6, 1-7, 2-6, 3-6, or 3-7 of A ⁇ 42.
  • Other exemplary N-terminal epitopes start at residues 1-3 and end at residues 7-11 of A ⁇ .
  • Additional exemplary N-terminal epitopes include residues 2-4, 5, 6, 7 or 8 of A ⁇ , residues 3-5, 6, 7, 8 or 9 of A ⁇ , or residues 4-7, 8, 9 or 10 of A ⁇ 42.
  • C-terminal epitopes are epitopes or antigenic determinants comprising residues located within the central or mid-portion of the A ⁇ peptide. Additional exemplary epitopes or antigenic determinants include residues 33-40 or 33-42 of A ⁇ . Such epitopes can be referred to as "C-terminal epitopes”.
  • Capturing soluble A ⁇ refers to binding of soluble A ⁇ which is present in the plasma, e.g. , as part of protein complexes or in the central nervous system, by an immunoglobulin, thereby preventing accumulation of A ⁇ and/or promoting removal of A ⁇ from the CNS.
  • effector function refers to an activity that resides in the Fc region of an antibody (e.g ., an IgG antibody) and includes, for example, the ability of the antibody to bind effector molecules such as complement and/or Fc receptors, which can control several immune functions of the antibody such as effector cell activity, lysis, complement-mediated activity, antibody clearance, and antibody half-life.
  • an antibody e.g ., an IgG antibody
  • effector function refers to an activity that resides in the Fc region of an antibody (e.g ., an IgG antibody) and includes, for example, the ability of the antibody to bind effector molecules such as complement and/or Fc receptors, which can control several immune functions of the antibody such as effector cell activity, lysis, complement-mediated activity, antibody clearance, and antibody half-life.
  • effector molecule refers to a molecule that is capable of binding to the Fc region of an antibody (e.g ., an IgG antibody) including, but not limited to, a complement protein or a Fc receptor.
  • Light chains are classified as either kappa or lambda and are about 230 residues in length.
  • Heavy chains are classified as gamma ( ⁇ ), mu ( ⁇ ), alpha ( ⁇ ), delta ( ⁇ ), or epsilon ( ⁇ ), are about 450-600 residues in length, and define the antibody's isotype as IgG, IgM, IgA, IgD and IgE, respectively.
  • Both heavy and light chains are folded into domains.
  • domain refers to a globular region of a protein, for example, an immunoglobulin or antibody.
  • Immunoglobulin or antibody domains include, for example, three or four peptide loops stabilized by ⁇ -pleated sheet and an interchain disulfide bond.
  • Intact light chains have, for example, two domains (V L and C L ) and intact heavy chains have, for example, four or five domains (V H , C H 1, C H 2, and C H 3).
  • Epitope specificity of an antibody can be determined, for example, by forming a phage display library in which different members of the library display different subsequences of A ⁇ . The phage display library is then screened for members specifically bind to an antibody under test. A family of sequences is selected and isolated. Typically, such a family contains a common core sequence, and varying lengths of flanking sequences in different members. The shortest core sequence showing specific binding to the antibody defines the epitope bound by the antibody. Antibodies can also be tested for epitope specificity in a competition assay with an antibody whose epitope specificity has already been determined.
  • Antibodies that specifically bind to a preferred segment of A ⁇ without binding to other regions of A ⁇ have a number of advantages relative to monoclonal antibodies binding to other regions or polyclonal sera to intact A ⁇ .
  • dosages of antibodies that specifically bind to preferred segments contain a higher molar dosage of antibodies effective in clearing amyloid plaques.
  • antibodies specifically binding to preferred segments can induce a clearing response against amyloid deposits without inducing a clearing response against intact APP polypeptide, thereby reducing the potential side effects.
  • Rabbits or guinea pigs are typically used for making polyclonal antibodies.
  • Exemplary preparation of polyclonal antibodies, e.g., for passive protection, can be performed as follows. 125 non-transgenic mice are immunized with 100 ⁇ g A ⁇ 1-42, plus CFA/IFA adjuvant, and euthanized at 4-5 months. Blood is collected from immunized mice. IgG is separated from other blood components. Antibody specific for the immunogen may be partially purified by affinity chromatography. An average of about 0.5-1 mg of immunogen-specific antibody is obtained per mouse, giving a total of 60-120 mg.
  • Residues which are "adjacent to a CDR region” include amino acid residues in positions immediately adjacent to one or more of the CDRs in the primary sequence of the humanized immunoglobulin chain, for example, in positions immediately adjacent to a CDR as defined by Kabat, or a CDR as defined by Chothia (See e.g., Chothia and Lesk JMB 196:901 (1987 )). These amino acids are particularly likely to interact with the amino acids in the CDRs and, if chosen from the acceptor, to distort the donor CDRs and reduce Affinity. Moreover, the adjacent amino acids may interact directly with the antigen ( Amit et al., Science, 233:747 (1986 ), ) and selecting these amino acids from the donor may be desirable to keep all the antigen contacts that provide affinity in the original antibody.
  • Residues that "otherwise interact with a CDR region” include those that are determined by secondary structural analysis to be in a spatial orientation sufficient to affect a CDR region.
  • residues that "otherwise interact with a CDR region” are identified by analyzing a three-dimensional model of the donor immunoglobulin (e.g ., a computer-generated model).
  • a three-dimensional model typically of the original donor antibody, shows that certain amino acids outside of the CDRs are close to the CDRs and have a good probability of interacting with amino acids in the CDRs by hydrogen bonding, Van der Waals forces, hydrophobic interactions, etc.
  • the donor immunoglobulin amino acid rather than the acceptor immunoglobulin amino acid may be selected.
  • Affinity maturation techniques can be used to alter the CDR region(s) followed by screening of the resultant binding molecules for the desired change in binding.
  • the method may also be used to alter the donor CDR, typically a mouse CDR, to be less immunogenic such that a potential human anti-mouse antibody (HAMA) response is minimized or avoided.
  • HAMA human anti-mouse antibody
  • changes in binding affinity as well as immunogenicity can be monitored and scored such that an antibody optimized for the best combined binding and low immunogenicity are achieved (see, e.g ., U.S. Pat. No. 6,656,467 and U.S. Pat. Pub. US20020164326A1 ).
  • acceptor human framework amino acids that are "rare" for a human immunoglobulin at that position. These amino acids can be substituted with amino acids from the equivalent position of the mouse donor antibody or from the equivalent positions of more typical human immunoglobulins. For example, substitution may be desirable when the amino acid in a human framework region of the acceptor immunoglobulin is rare for that position and the corresponding amino acid in the donor immunoglobulin is common for that position in human immunoglobulin sequences; or when the amino acid in the acceptor immunoglobulin is rare for that position and the corresponding amino acid in the donor immunoglobulin is also rare, relative to other human sequences.
  • Rare mouse residues are identified by comparing the donor VL and/or VH sequences with the sequences of other members of the subgroup to which the donor VL and/or VH sequences belong (according to Kabat) and identifying the residue positions which differ from the consensus. These donor specific differences may point to somatic mutations which enhance activity. Unusual or rare residues close to the binding site may possibly contact the antigen, making it desirable to retain the mouse residue. However, if the unusual mouse residue is not important for binding, use of the corresponding acceptor residue is preferred as the mouse residue may create immunogenic neoepitopes in the humanized antibody. In the situation where an unusual residue in the donor sequence is actually a common residue in the corresponding acceptor sequence, the preferred residue is clearly the acceptor residue.
  • a humanized antibody of the present invention has structural features as described herein, and specifically binds to an epitope within residues 13-28 of A ⁇ , e.g., comprising residues 19-22 of A ⁇ ).
  • nucleic acid sequences will encode each immunoglobulin amino acid sequence.
  • the desired nucleic acid sequences can be produced by de novo solid-phase DNA synthesis or by PCR mutagenesis of an earlier prepared variant of the desired polynucleotide.
  • Oligonucleotide-mediated mutagenesis is a preferred method for preparing substitution, deletion and insertion variants of target polypeptide DNA. See Adelman et al., DNA 2:183 (1983). Briefly, the target polypeptide DNA is altered by hybridizing an oligonucleotide encoding the desired mutation to a single-stranded DNA template. After hybridization, a DNA polymerase is used to synthesize an entire second complementary strand of the template that incorporates the oligonucleotide primer, and encodes the selected alteration in the target polypeptide DNA.
  • a humanized antibody of the invention includes the 15C11 VH region linked to an IgG1 constant region. In another embodiment, a humanized antibody of the invention includes the 15C11 VH region linked to an IgG4 constant region.
  • antibody fragments are also contemplated within the scope of the instant invention.
  • fragments of non-human, and/or chimeric antibodies are provided.
  • fragments of humanized antibodies are provided. Typically, these fragments exhibit specific binding to antigen with an affinity of at least 10 7 , and more typically 10 8 or 10 9 M -1 .
  • Humanized antibody fragments include separate heavy chains, light chains, Fab, Fab', F(ab')2, Fabc, and Fv. Fragments are produced by recombinant DNA techniques, or by enzymatic or chemical separation of intact immunoglobulins.
  • Profiles are likewise generated at successive positions along the antigenic peptide.
  • the combined profile, or epitope map, (reflecting substitution at each position with all 19 non-native residues) can then be compared to a map similarly generated for a second antibody.
  • Substantially similar or identical maps indicate that antibodies being compared have the same or similar epitope specificity.
  • mice are injected intraperitoneally as needed over a 4 month period to maintain a circulating antibody concentration measured by ELISA titer of greater than 1/1000 defined by ELISA to A ⁇ 42 or other immunogen. Titers are monitored and mice are euthanized at the end of 6 months of injections. Histochemistry, A ⁇ levels and toxicology are performed post mortem. Ten mice are used per group.
  • An antibody's ability to improve cognition in the CFC assay is further believed to be a strong indicator or predictor of the antibody's ultimate human therapeutic efficacy (in particular, efficacy in rapidly improving cognition in a patient). Accordingly, a comparison of A ⁇ antibody binding preferences and/or affinities leads to the identification of certain antibodies as candidates for use in the therapeutic methods of the invention, in particular, for use in method for effecting rapid improvement in cognition in a patient.
  • the binding of an antibody to one or more soluble, oligomeric A ⁇ species or to monomeric A ⁇ can be determined qualitatively, quantitatively, or combination of both.
  • any technique capable of distinguishing oligomeric A ⁇ species from monomeric A ⁇ in an A ⁇ preparation comprising the species can be used.
  • one or more of immunoprecipitation, electrophoretic separation, and chromatographic separation e.g ., liquid chromatography
  • chromatographic separation e.g ., liquid chromatography
  • the CFC assay provides a method for independently testing and/or validating the therapeutic effect of agents for preventing or treating a cognitive disease or disorder, and in particular, a disease or disorder affecting one or more regions of the brains, e.g., the hippocampus, subiculum, cingulated cortex, prefrontal cortex, perirhinal cortex, sensory cortex, and medial temporal lobe.
  • a cognitive disease or disorder e.g., the hippocampus, subiculum, cingulated cortex, prefrontal cortex, perirhinal cortex, sensory cortex, and medial temporal lobe.
  • the aversive response is usually characterized on the first day of testing to determine a baseline for unconditioned fear with aversive response results on subsequent test days (e.g ., freezing in the same context but in the absence of the aversive stimulus and/or freezing in presence of the cue but in the absence of the aversive experience) being characterized as contextually conditioned fear.
  • test animals are typically tested separately by independent technicians and scored over time. Additional experimental design details can be found in the art, for example, in Crawley, JN, What's Wrong with my Mouse; Behavioral Phenotyping of Transgenic and Knockout Mice, Wiley-Liss, NY (2000 ).
  • transgenic mouse strains are available that overexpress APP and develop amyloid plaque pathology and/or develop cognitive deficits that are characteristic of Alzheimer's disease (see for example, Games et al., supra, Johnson-Wood et al., Proc. Natl. Acad. Sci. USA 94:1550 (1997 ); Masliah E and Rockenstein E. (2000) JNeural Transm Suppl.;59:175-83 ) .
  • the animal model exhibits a prominent cognitive deficit associated with learning or memory in addition to the neurodegenerative pathology that associated with a amyloidogenic disorder. More preferably, the cognitive deficit progressively worsens with increasing age, such that the disease progression in the model animal parallels the disease progression in a subject suffering from the amyloidogenic disorder.
  • Conditional fear conditioning and other in vivo assays to test the functionality of the antibodies described herein may be performed using wild-type mice or mice having a certain genetic alteration leading to impaired memory or mouse models of neurodegenerative disease, e.g., Alzheimer's disease, including mouse models which display elevated levels of soluble A ⁇ in the cerebrospinal fluid (CSF) or plasma.
  • animal models for Alzheimer's disease include transgenic mice that overexpress the "Swedish" mutation of human amyloid precursor protein ( hAPPswe; Tg2576) which show age-dependent memory deficits and plaques ( Hsiao et al. (1996) Science 274:99-102 ).
  • the in vivo functionality of the antibodies described herein can also be tested using PDAPP transgenic mice, which express a mutant form of human APP (APP V71F ) and develop Alzheimer's disease at a young age ( Bard, et al. (2000) Nature Medicine 6:916-919 ; Masliah E, et al. (1996) JNeurosci. 15;16(18):5795-811 ).
  • Other mouse models for Alzheimer's disease include the PSAPP mouse, a doubly transgenic mouse (PSAPP) overexpressing mutant APP and PS1 transgenes, described in Holcomb, et al. (1998) Nature Medicine 4:97-110 , and the PS-1 mutant mouse, described in Duff, et al. (1996) Nature 383, 710-713 .
  • PSAPP doubly transgenic mouse
  • PSAPP a doubly transgenic mouse
  • PS-1 mutant mouse described in Duff, et al. (1996) Nature 383, 710-713 .
  • the effector function of an antibody resides in the constant or Fc region of the molecule which can mediate binding to various effector molecules, e.g., complement proteins or Fc receptors.
  • the binding of complement to the Fc region is important, for example, in the opsonization and lysis of cell pathogens and the activation of inflammatory responses.
  • the above-mentioned immune functions may be desirable.
  • various aspects of the effector function of the molecule including enhancing or suppressing various reactions of the immune system, with beneficial effects in diagnosis and therapy, are achieved.
  • Antibodies of the invention can be produced which react only with certain types of Fc receptors, for example, the antibodies of the invention can be modified to bind to only certain Fc receptors, or if desired, lack Fc receptor binding entirely, by deletion or alteration of the Fc receptor binding site located in the Fc region of the antibody.
  • Other desirable alterations of the Fc region of an antibody of the invention are cataloged below.
  • the EU numbering system ie . as in the EU index of Kabat et al., supra
  • amino acid residue(s) of the Fc region e.g ., of an IgG antibody
  • the numbering system is also employed to compare antibodies across species such that a desired effector function observed in, for example, a mouse antibody, can then be systematically engineered into a human, humanized, or chimeric antibody of the invention.
  • a comparison of the sequence of these proteins in the hinge-link region shows that the sequence from EU numbering positions 234 to 238, i.e., Leu-Leu-Gly-Gly-Pro in the strong binders becomes Leu-Glu-Gly-Gly-Pro in mouse gamma 2b, i.e., weak binders. Accordingly, a corresponding change in a human antibody hinge sequence can be made if reduced Fc ⁇ I receptor binding is desired. It is understood that other alterations can be made to achieve the same or similar results. For example, the affinity of FcyRI binding can be altered by replacing the specified residue with a residue having an inappropriate functional group on its sidechain, or by introducing a charged functional group (e.g. , Glu or Asp) or for example an aromatic non-polar residue ( e.g ., Phe, Tyr, or Trp).
  • a charged functional group e.g. , Glu or Asp
  • an aromatic non-polar residue e.g ., Phe, Tyr,
  • an antibody of the invention is a humanized antibody including amino acid alterations at one or more EU positions 234, 235, 236 and 237.
  • a humanized antibody includes amino acid alterations at EU positions 234 and 237 of the hinge link region derived from IgG1 (i.e., L234A and G237A).
  • the first component of the complement system, Cl comprises three proteins known as Clq, Clr and Cls which bind tightly together. It has been shown that Clq is responsible for binding of the three protein complex to an antibody.
  • the Clq binding activity of an antibody can be altered by providing an antibody with an altered CH 2 domain in which at least one of the amino acid residues at EU amino acid positions 318, 320, and 322 of the heavy chain has been changed to a residue having a different side chain.
  • suitable alterations for altering, e.g., reducing or abolishing specific Clq-binding to an antibody include changing any one of residues at EU positions 318 (Glu), 320 (Lys) and 322 (Lys), to Ala.
  • Immune responses against amyloid deposits can also be induced by administration of nucleic acids encoding antibodies and their component chains used for passive immunization.
  • nucleic acids can be DNA or RNA.
  • a nucleic acid segment encoding an immunogen is typically linked to regulatory elements, such as a promoter and enhancer, that allow expression of the DNA segment in the intended target cells of a patient.
  • regulatory elements such as a promoter and enhancer
  • exemplary promoter and enhancer elements include those from light or heavy chain immunoglobulin genes and/or the CMV major intermediate early promoter and enhancer ( Stinski, U.S. Patent Nos. 5,168,062 and 5,385,839 ).
  • the linked regulatory elements and coding sequences are often cloned into a vector.
  • the two chains can be cloned in the same or separate vectors.
  • the isotype of the antibody is IgG4.
  • an antibody of the invention is engineered to have an isotype having reduced effector function (e.g ., reduced Fc-mediated phagocytosis, reduced ability to opsonize plaques etc. ).
  • an antibody of the invention is a humanized 15C11 antibody having an IgG4 isotype.
  • the present invention provides antibodies for use in methods for effecting rapid improvement in cognition in a patient having or at risk for an suffering from an A ⁇ -related disease or disorder or amyloidogenic disease or disorder (e.g ., AD).
  • the methods feature administering an effective dose of an antibody agent such that rapid improvement in cognition is achieved.
  • improvement in one or more cognitive deficits in the patient e.g ., procedural learning and/or memory, deficits
  • the cognitive deficit can be an impairment in explicit memory (also known as "declarative" or "working" memory), which is defined as the ability to store and retrieve specific information that is available to consciousness and which can therefore be expressed by language ( e.g. the ability to remember a specific fact or event).
  • the cognitive deficit can be an impairment in procedural memory (also known as "implicit” or “contextual” memory), which is defined as the ability to acquire, retain, and retrieve general information or knowledge that is not available to consciousness and which requires the learning of skills, associations, habits, or complex reflexes to be expressed, e.g. the ability to remember how to execute a specific task.
  • procedural memory also known as "implicit” or “contextual” memory
  • Individuals suffering from procedural memory deficits are much more impaired in their ability to function normally. As such, treatments which are effective in improving deficits in procedural memory are highly desirable and advantageous.
  • Indicators of patients having probable AD include, but are not limited to, patients (1) having dementia, (2) of an age of 40-90 years old, (3) cognitive deficits, e.g., in two or more cognitive domains, (4) progression of deficits for more than six months, (5) consciousness undisturbed, and/or (6) absence of other reasonable diagnoses.
  • MRI three-dimensional magnetic resonance imaging
  • PET positron emission tomography
  • SPECT single-photon emission computed tomography
  • Indicators of patients having probable AD include, but are not limited to, patients (1) having dementia, (2) of an age of 40-90 years old, (3) cognitive deficits, e.g., in two or more cognitive domains, (4) progression of deficits for more than six months, (5) consciousness undisturbed, and/or (6) absence of other reasonable diagnoses.
  • AD Alzheimer's disease
  • Common symptoms of AD include cognitive deficits that affect the performance of routine skills or tasks, problems with language, disorientation to time or place, poor or decreased judgement, impairments in abstract thought, loss of motor control, mood or behaviour alteration, personality change, or loss of initiative.
  • the number deficits or the degree of the cognitive deficit displayed by the patient usually reflects the extent to which the disease has progressed. For example, the patient may exhibit only a mild cognitive impairment, such that the patient exhibits problems with memory (e.g. contextual memory) but is otherwise able to function well.
  • ADAS-Cog Alzheimer's disease Assessment Scale-Cognitive
  • the ADAS-Cog is 11-part test that takes 30 minutes to complete.
  • the ADAS-Cog is a preferred brief exam for the study of language and memory skills. See Rosen et al. (1984) Am J Psychiatry. 141(11):1356-64 ; Ihl et al. (2000) Neuropsychobiol. 41(2):102-7 ; and Weyer et al. (1997) Int Psychogeriatr. 9(2):123-38 .
  • the Cambridge Neuropsychological Test Automated Battery (CANTAB) is used for the assessment of cognitive deficits in humans with neurodegenerative diseases or brain damage. It consists of thirteen interrelated computerized tests of memory, attention, and executive function, and is administered via a touch sensitive screen from a personal computer. The tests are language and largely culture free, and have shown to be highly sensitive in the early detection and routine screening of Alzheimer's disease. See Swainson et al. (2001) Dement Geriatr Cogn Disord.;12:265-280 ; and Fray and Robbins (1996) Neurotoxicol Teratol. 18(4):499-504 . Robbins et al. (1994) Dementia 5(5):266-81 .
  • the Seven-Minute Screen is a screening tool to help identify patients who should be evaluated for Alzheimer's disease.
  • the screening tool is highly sensitive to the early signs of AD, using a series of questions to assess different types of intellectual functionality.
  • the test consists of 4 sets of questions that focus on orientation, memory, visuospatial skills and expressive language. It can distinguish between cognitive changes due to the normal aging process and cognitive deficits due to dementia. See Solomon and Pendlebury (1998) Fam Med. 30(4):265-71 , Solomon et al. (1998) Arch Neurol. 55(3):349-55 .
  • agent reduces or eliminates myocognitive impairment in patients that have not yet developed characteristic Alzheimer's pathology.
  • An amount adequate to accomplish therapeutic or prophylactic treatment is defined as a therapeutically- or prophylactically-effective dose.
  • agents are usually administered in several dosages until a sufficient immune response has been achieved.
  • the term "immune response” or "immunological response” includes the development of a humoral (antibody mediated) and/or a cellular (mediated by antigen-specific T cells or their secretion products) response directed against an antigen in a recipient subject.
  • Such a response can be an active response, i.e ., induced by administration of immunogen, or a passive response, i.e. , induced by administration of immunoglobulin or antibody or primed T-cells.
  • the immune response is monitored and repeated dosages are given if the immune response starts to wane.
  • Effective doses of the compositions of the present invention, for the treatment of the above described conditions vary depending upon many different factors, including means of administration, target site, physiological state of the patient, whether the patient is human or an animal, other medications administered, and whether treatment is prophylactic or therapeutic.
  • the patient is a human but non-human mammals including transgenic mammals can also be treated. Treatment dosages need to be titrated to optimize safety and efficacy.
  • the dosage ranges from about 0.0001 to 100 mg/kg, and more usually 0.01 to 5 mg/kg (e.g., 0.02 mg/kg, 0.25 mg/kg, 0.5 mg/kg, 0.75 mg/kg, 1mg/kg, 2 mg/kg, etc.), of the host body weight.
  • dosages can be 1 mg/kg body weight or 10 mg/kg body weight or within the range of 1-10 mg/kg, preferably at least 1 mg/kg.
  • dosages can be 0.5 mg/kg body weight or 15 mg/kg body weight or within the range of 0.5-15 mg/kg, preferably at least 1 mg/kg.
  • dosages can be 0.5 mg/kg body weight or 20 mg/kg body weight or within the range of 0.5-20 mg/kg, preferably at least 1 mg/kg. In another example, dosages can be 0.5 mg/kg body weight or 30 mg/kg body weight or within the range of 0.5-30 mg/kg, preferably at least 1 mg/kg. In a preferred example, dosages can be about 30 kg/mg. In a particularly preferred example, the 15C11 antibody is administered intraperitoneally at a dose range from approximately 0.3 mg/kg to approximately 30 mg/kg.
  • Antibody is usually administered on multiple occasions. Intervals between single dosages can be weekly, monthly or yearly. Intervals can also be irregular as indicated by measuring blood levels of antibody to A ⁇ in the patient. In some methods, dosage is adjusted to achieve a plasma antibody concentration of 1-1000 ⁇ g/ml and in some methods 25-300 ⁇ g/ml. Alternatively, antibody can be administered as a sustained release formulation, in which case less frequent administration is required. Dosage and frequency vary depending on the half-life of the antibody in the patient. In general, humanized antibodies show the longest half-life, followed by chimeric antibodies and nonhuman antibodies.
  • treatment can begin at any age (e.g., 10, 20, 30). Usually, however, it is not necessary to begin treatment until a patient reaches 40, 50, 60 or 70. Treatment typically involves multiple dosages over a period of time. Treatment can be monitored by assaying antibody levels over time. If the response falls, a booster dosage is indicated. In the case of potential Down's syndrome patients, treatment can begin antenatally by administering therapeutic agent to the mother or shortly after birth.
  • a relatively high dosage e.g., from about 1 to 200 mg of antibody per dose, with dosages of from 5 to 25 mg being more commonly used
  • a relatively short intervals is sometimes required until progression of the disease is reduced or terminated, and preferably until the patient shows partial or complete amelioration of symptoms of disease. Thereafter, the patient can be administered a prophylactic regime.
  • Doses for nucleic acids encoding antibodies range from about 10 ng to 1 g, 100 ng to 100 mg, 1 ⁇ g to 10 mg, or 30-300 ⁇ g DNA per patient.
  • Doses for infectious viral vectors vary from 10-100, or more, virions per dose.
  • Agents of the invention can also be administered in combination with other agents that enhance access of the therapeutic agent to a target cell or tissue, for example, liposomes and the like. Coadministering such agents can decrease the dosage of a therapeutic agent (e.g., therapeutic antibody or antibody chain) needed to achieve a desired effect.
  • a therapeutic agent e.g., therapeutic antibody or antibody chain
  • compositions or formulation may also include other carriers, adjuvants, or nontoxic, nontherapeutic, nonimmunogenic stabilizers and the like.
  • agents of the invention can be administered as injectable dosages of a solution or suspension of the substance in a physiologically acceptable diluent with a pharmaceutical carrier that can be a sterile liquid such as water oils, saline, glycerol, or ethanol.
  • a pharmaceutical carrier that can be a sterile liquid such as water oils, saline, glycerol, or ethanol.
  • auxiliary substances such as wetting or emulsifying agents, surfactants, pH buffering substances and the like can be present in compositions.
  • Other components of pharmaceutical compositions are those of petroleum, animal, vegetable, or synthetic origin, for example, peanut oil, soybean oil, and mineral oil.
  • glycols such as propylene glycol or polyethylene glycol are preferred liquid carriers, particularly for injectable solutions.
  • Antibodies can be administered in the form of a depot injection or implant preparation, which can be formulated in such a manner as to permit a sustained release of the active ingredient.
  • An exemplary composition comprises monoclonal antibody at 5 mg/mL, formulated in aqueous buffer consisting of 50 mM L-histidine, 150 mM NaCl, adjusted to pH 6.0 with HCl.
  • compositions are prepared as injectables, either as liquid solutions or suspensions; solid forms suitable for solution in, or suspension in, liquid vehicles prior to injection can also be prepared.
  • the preparation also can be emulsified or encapsulated in liposomes or micro particles such as polylactide, polyglycolide, or copolymer for enhanced adjuvant effect, as discussed above (see Langer, Science 249: 1527 (1990 ) and Hanes, Advanced Drug Delivery Reviews 28:97 (1997 )).
  • the agents of this invention can be administered in the form of a depot injection or implant preparation, which can be formulated in such a manner as to permit a sustained or pulsatile release of the active ingredient.
  • binders and carriers include, for example, polyalkylene glycols or triglycerides; such suppositories can be formed from mixtures containing the active ingredient in the range of 0.5% to 10%, preferably 1%-2%.
  • Oral formulations include excipients, such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, and magnesium carbonate. These compositions take the form of solutions, suspensions, tablets, pills, capsules, sustained release formulations or powders and contain 10%-95% of active ingredient, preferably 25%-70%.
  • Topical application can result in transdermal or intradermal delivery.
  • Topical administration can be facilitated by co-administration of the agent with cholera toxin or detoxified derivatives or subunits thereof or other similar bacterial toxins (See Glenn et al., Nature 391, 851 (1998 )).
  • Co-administration can be achieved by using the components as a mixture or as linked molecules obtained by chemical crosslinking or expression as a fusion protein.
  • the disclosure provides methods of monitoring treatment in a patient suffering from or susceptible to Alzheimer's, i.e ., for monitoring a course of treatment being administered to a patient.
  • the methods can be used to monitor both therapeutic treatment on symptomatic patients and prophylactic treatment on asymptomatic patients.
  • the methods are useful for monitoring passive immunization (e.g. , measuring level of administered antibody).
  • a patient who is not presently receiving treatment but has undergone a previous course of treatment is monitored for antibody levels or profiles to determine whether a resumption of treatment is required.
  • the measured level or profile in the patient can be compared with a value previously achieved in the patient after a previous course of treatment. A significant decrease relative to the previous measurement (i.e ., greater than a typical margin of error in repeat measurements of the same sample) is an indication that treatment can be resumed.
  • the value measured in a patient can be compared with a control value (mean plus standard deviation) determined in a population of patients after undergoing a course of treatment.
  • the measured value in a patient can be compared with a control value in populations of prophylactically treated patients who remain free of symptoms of disease, or populations of therapeutically treated patients who show amelioration of disease characteristics.
  • a significant decrease relative to the control level i.e ., more than a standard deviation is an indicator that treatment should be resumed in a patient.
  • Additional methods include monitoring, over the course of treatment, any art-recognized physiologic symptom (e.g., physical or mental symptom) routinely relied on by researchers or physicians to diagnose or monitor amyloidogenic diseases (e.g., Alzheimer's disease).
  • physiologic symptom e.g., physical or mental symptom
  • amyloidogenic diseases e.g., Alzheimer's disease
  • cognitive impairment can be monitored by determining a patient's score on the Mini-Mental State Exam in accordance with convention throughout the course of treatment.
  • kits for performing the monitoring methods described above.
  • such kits contain an agent that specifically binds to antibodies to A ⁇ .
  • the kit can also include a label.
  • the label is typically in the form of labeled anti-idiotypic antibodies.
  • the agent can be supplied prebound to a solid phase, such as to the wells of a microtiter dish.
  • Kits also typically contain labeling providing directions for use of the kit.
  • the labeling may also include a chart or other correspondence regime correlating levels of measured label with levels of antibodies to A ⁇ .
  • labeling refers to any written or recorded material that is attached to, or otherwise accompanies a kit at any time during its manufacture, transport, sale or use.
  • the term labeling encompasses advertising leaflets and brochures, packaging materials, instructions, audio or videocassettes, computer discs, as well as writing imprinted directly on kits.
  • an antibody or immunoglobulin sequence comprising a VL and/or VH sequence as set forth in any one of SEQ ID NOs: 1-9 can comprise (or encode) either the full sequence or can comprise the mature sequence (i.e., mature peptide without the signal or leader peptide).
  • antibodies including 15C11 were administered to wild type and Tg2576 mice at 3 mg/kg, 10 mg/kg, and 30 mg/kg. Mice were assayed for contextual fear conditioning as described herein.
  • mice displaying memory deficit reversal did so within a short time period. Without being bound by the following, this rapid improvement in cognition in mice administered 15C11 suggest a mechanism of action of 15C11 that involves the capture of soluble A ⁇ in the blood and the subsequent removal of A ⁇ from the CNS into the plasma.
  • the ability of various antibodies (including 15C11) to capture soluble A ⁇ was assayed as follows. Various concentrations of antibody (up to 10 ⁇ g/ml) were incubated with 50,000 CPM of 125 I-A ⁇ 1-42 (or 125 I-A ⁇ 1-40). The concentration of antibody sufficient to bind 25% of the radioactive counts was determined in a capture radioimmunoassay. Certain antibodies did not bind 25% of the counts at the highest concentration tested (i.e., 10 ⁇ g/ml). For such antibodies, the percentage of counts bound at 10 ⁇ g/ml was determined. At 3 ⁇ g/ml, 15C11 bound 25% of the radioactive counts ( i.e ., 125 I-A ⁇ ).
  • This capture was significant as compared to other monoclonal antibodies raised against central A ⁇ fragments ( e.g ., A ⁇ 13-28 or A ⁇ 17-28).
  • the range of concentrations necessary to capture 25% of the labeled A ⁇ for such antibodies is from about 0.1 ⁇ g/ml to 10 ⁇ g/ml with some antibodies capturing less than 25% labeled A ⁇ ( e.g. , 10-20%) when assayed at 10 ⁇ g/ml.
  • 15C11 exhibited preferential affinity for oligomeric A ⁇ species as compared to monomeric A ⁇ . This preferential binding correlates with efficacy in the CFC animal model described above and is predictive of therapeutic efficacy of the antibody ( e.g ., effecting rapid improvement in cognition) in vivo .
  • both light and heavy chains comprise the domains FR1, CDR1, FR2, CDR2, FR3, CDR3 and FR4.
  • Example IV In vitro Efficacy of a Various A ⁇ Antibodies: Binding Soluble, Oligomeric A ⁇
  • the A ⁇ preparation was derived from synthetic A ⁇ oligimers substantially as follows:
  • Portions of the A ⁇ preparation were then each contacted with a test immunological reagent, in this case antibodies, and the A ⁇ monomers and one or more A ⁇ oligomers which bound to the test immunological reagent were extracted from the A ⁇ preparation by immunoprecipitation.
  • the various immunoprecipitates were separated by gel electrophoresis and immunoblotted with the 3D6 antibody substantially as follows. Immunoprecipitate samples of Figure 6 were diluted in sample buffer and separated by SDS-PAGE on a 16% Tricine gel. The protein was transferred to nitrocellulose membranes, the membranes boiled in PBS, and then blocked overnight at 4°C in a solution of TBS/Tween/5% Carnation dry milk.
  • the membranes were then incubated with 3D6, a mouse monoclonal A ⁇ antibody to residues 1-5.
  • the membranes were incubated with anti-mouse Ig-HRP, developed using ECL Plus, and visualized using film.
  • Molecular mass was estimated by SeeBlueTM Plus2 molecular weight markers.
  • a “+” notation indicates an observation of increased cognition upon treatment with the antibody
  • a “-” notation indicates an observation of no change in cognition upon treatment with the antibody
  • a "+/-” notation indicates an observation of a trend of increased cognition upon treatment with the antibody but which is not statistically significant enough to be indicated as an observation of increased cognition
  • "ND” notation indicates no CFC assay data available or compared for this antibody.
  • an increased binding of an A ⁇ antibody for A ⁇ dimers or higher ordered oligomers in the A ⁇ preparation predicts that the A ⁇ antibody has therapeutic efficacy for the treatment of Alzheimer's disease.
  • a ⁇ antibodies 3D6, 15C11, 10D5, 12A11 and 266 exhibited preferential binding for oligomeric A ⁇ species as compared to monomeric A ⁇ with 12A11 exhibiting the most significant preferential binding to oligomeric A ⁇ . Accordingly, these antibodies are predicted to have therapeutic efficacy in the treatment cognitive deficits , e.g ., those associated with AD.
  • a phase II trial is performed to determine therapeutic efficacy.
  • Patients with early to mid Alzheimer's Disease defined using Alzheimer's disease and Related Disorders Association (ADRDA) criteria for probable AD are selected. Suitable patients score in the 12-26 range on the Mini-Mental State Exam (MMSE). Other selection criteria are whether patients are likely to survive for the duration of the study and lack complicating issues such as use of concomitant medications that may interfere.
  • Baseline evaluations of patient function are made using classic psychometric measures, such as the MMSE, and the ADAS, which is a comprehensive scale for evaluating patients with Alzheimer's Disease status and function. These psychometric scales provide a measure of progression of the Alzheimer's condition. Suitable qualitative life scales can also be used to monitor treatment. Disease progression can also be monitored by MRI. Blood profiles of patients can also be monitored including assays of immunogen-specific antibodies and T-cells responses.
  • patients Following baseline measurements, patients begin receiving treatment. They are randomized and treated with either therapeutic agent or placebo in a blinded fashion. Patients are monitored at least every six months. Efficacy is determined by a significant reduction in progression of a treatment group relative to a placebo group.
  • a second phase II trial is performed to evaluate conversion of patients from non-Alzheimer's Disease early memory loss, sometimes referred to as age-associated memory impairment (AAMI) or mild cognitive impairment (MCI), to probable Alzheimer's disease as defined as by ADRDA criteria.
  • Patients with high risk for conversion to Alzheimer's Disease are selected from a non-clinical population by screening reference populations for early signs of memory loss or other difficulties associated with pre-Alzheimer's symptomatology, a family history of Alzheimer's Disease, genetic risk factors, age, sex, and other features found to predict high-risk for Alzheimer's Disease.
  • Baseline scores on suitable metrics including the MMSE and the ADAS together with other metrics designed to evaluate a more normal population are collected.
  • patient populations are divided into suitable groups with placebo comparison against dosing alternatives with the agent. These patient populations are followed at intervals of about six months, and the endpoint for each patient is whether or not he or she converts to probable Alzheimer's Disease as defined by ADRDA criteria at the end of the observation.

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